B-cell malignancies, such as lymphoma and leukemia, occur when the regulation of B-cell differentiation and activation is disrupted. Malignancies of mature B-cells include follicular lymphoma, mantle-cell lymphoma, Burkitt lymphoma, multiple myeloma, diffuse large B-cell lymphoma, Hodgkin lymphoma, lymphoplasmacytic lymphoma, marginal-zone lymphoma, and chronic lymphocytic leukemia (Shaffer et al., Nature Reviews Immunology, 2: 920-933 (2002)). Standard therapies such as chemotherapy, therapeutic monoclonal antibodies (e.g., Rituximab (RITUXAN™)), and allogeneic stem cell transplantation (alloHSCT) do not cure B-cell malignancies (see, e.g., Dreger et al., Leukemia, 21(1): 12-17 (2007); Gribben, J. G., Blood, 109(11): 4617-4626 (2007); and Armitage, J. O., Blood, 110(1): 29-36 (2007)). In particular, monoclonal antibodies are not curative as single agents, and alloHSCT is associated with high levels of mortality and morbidity (see, e.g., Dreger et al., supra, Armitage et al., supra, and McLaughlin et al., Journal of Clinical Oncology, 16(8): 2825-2833 (1998)).
T-cells can be genetically modified to express chimeric antigen receptors (CARs), which are fusion proteins comprised of an antigen recognition moiety and T-cell activation domains (see, e.g., Kershaw et al., supra, Eshhar et al., Proc. Natl. Acad. Sci. USA, 90(2): 720-724 (1993), and Sadelain et al., Curr. Opin. Immunol., 21(2): 215-223 (2009)). For B-cell lineage malignancies, adoptive T-cell approaches that utilize CARs which target CD19 have been developed (see, e.g., Jensen et al., Biology of Blood and Marrow Transplantation, 16: 1245-1256 (2010); Kochenderfer et al., Blood, 116(20): 4099-4102 (2010); Porter et al., The New England Journal of Medicine, 365(8): 725-733 (2011); Savoldo et al., Journal of Clinical Investigation, 121(5): 1822-1826 (2011), Cooper et al., Blood, 101(4): 1637-1644 (2003); Brentjens et al., Nature Medicine, 9(3): 279-286 (2003); Kalos et al., Science Translational Medicine, 3(95): 95ra73 (2011); Cheadle et al., Journal of Immunology, 184(4): 1885-1896 (2010); Brentjens et al., Clinical Cancer Research, 13(18 Pt 1): 5426-5435 (2007); Kochenderfer et al., Blood, 116(19): 3875-3886 (2010); Brentjens et al., Blood, 118(18): 4817-4828 (2011); and Kochenderfer et al., Blood, Dec. 8, 2011 (epublication ahead of print (2012)). The B-cell antigen CD19 has been chosen as target for CARs because its expression is limited to normal and malignant B-cells (see, e.g., Nadler et al., Journal of Immunology, 131(1): 244-250 (1983)).
One disadvantage associated with the anti-CD19 CAR therapies reported to date is that they can induce significant toxicity associated with elevated levels of serum cytokines. The generation of human anti-mouse immune responses also is a potential risk associated with current anti-CD19 CARs, which contain murine sequences (see, e.g., Jensen et al., supra; Lamers et al., Blood, 117(1): 72-82 (2011); and Maus et al., Cancer Immunol Res, 2: 112-120 (2014)).
Thus, there remains a need for compositions that can be used in methods to treat B-cell malignancies which have reduced toxicity and immunogenicity in humans. This invention provides such compositions and methods.